An elevated level of plasma cholesterol in the form of low density lipoprotein is associated with an increased risk of atherosclerosis, one of the leading causes of death in the United States and western europe. It is generally accepted that reducing plasma cholesterol levels reduces the risk of atherosclerosis by reducing the extent of atherosclerotic plaque formation and may, in early stages of the disease, reverse plaque accumulation. Accordingly, individuals who are diagnosed as having hypercholesteremia (excessive plasma cholesterol) or a predisposition to hypercholesteremia, typically are advised to reduce their plasma cholesterol levels by dietary or pharmacological means. (See, e.g., Goodman & Gilman's The Pharmacological Basis of Therapeutics, 8th ed., Pergamon Press, N.Y., N.Y., pp. 874-896 (1990)).
Cholesterol is carried in the blood in the form of lipoprotein complexes such as very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL). LDL transports cholesterol from the blood to the subendothelial space of blood vessel walls. Within the subendothelial space, LDL is peroxidized into a modified form generally referred to as oxidized LDL. Peroxidation of LDL in the subendothelial space is believed to play a key role in atherogenesis due to excess uptake of the oxidized LDL by local macrophages and the concomitant transformation of the macrophages into foam cells. (Subbiah, M. T., et al., J. Clin. Endocrinol. and Metab. 77(4):1095-1097 (1993)). HDL protects against plaque formation and delays the onset of atherosclerotic symptoms by mediating the transport of cholesterol from the vessel wall to the liver in a process known as "reverse cholesterol transport", (See, e.g., U.S. Pat. No. 5,281,738, issued to Parker, R., et al., and references cited therein, the contents of which are incorporated herein by reference).
Numerous methods directed to reducing plasma LDL levels and/or increasing plasma HDL levels have been proposed for preventing atherosclerotic plaque formation and delaying the onset of atherosclerosis symptoms. In general, these methods involve daily administration of a pharmacological agent for reducing LDL levels or periodic plasma delipidation by means of a continuous flow filtration system (e.g., U.S. Pat. No. 4,895,558, issued to B. Cham, the contents of which are incorporated herein by reference).
Several types of pharmacological agents have been disclosed for reducing plasma LDL levels. In general, these agents act either by diminishing the production of lipoproteins or by enhancing the efficiency of their removal from plasma. Drugs that lower the concentration of plasma lipoproteins include inhibitors of HMG CoA (hydroxymethylglutaryl-CoA) reductase, the rate-controlling enzyme in the biosynthetic pathway of cholesterol. Exemplary HMG CoA reductase inhibitors include mevastatin, lovastatin, pravastatin and simvastatin. (see, e.g., Goodman & Gilman's The Pharmacological Basis of Therapeutics, supra., and references cited therein, and U.S. Pat. No. 5,278,171, the contents of which are incorporated herein by reference). Other agents that have met with varying degrees of success with respect to reducing plasma LDL levels include gemifibrozil, clofibrate, fenofibrate, cholestryamine, colestipol and nicotinic acid. (See, e.g., U.S. Pat. No. 5,112,827, issued to Saunders, Jr. et al., the contents of which are incorporated herein by reference, for a discussion of the mechanisms of action and undesirable side-effects associated with many of the foregoing agents).
Although methods utilizing at least some of the above-identified pharmacological agents and/or methods may favorably alter the LDL/HDL ratio in the plasma of hyperlipidemic patients, each of the foregoing methods requires substantial patient compliance, i.e., daily self-medication, to reap a therapeutic benefit. None of the above-identified references and/or patents disclose a method for treating a large population of subjects diagnosed as having a hyperlipidemia-associated condition, in which the therapeutic efficacy of the method is independent of patient compliance.